Generation of Genotypically Diverse R5 SHIVs as Tools in HIV-1 Vaccine Research

描述（由申请人提供）：本R24申请的目标是生成一组可靠的致病性R5 shiv，代表全球流行的HIV-1毒株，重点是助长HIV-1大流行的亚型C和CRF_AE。我们设想，这些概括了人类HIV免疫发病机制的新型shiv不仅可以作为临床前非人灵长类动物（NHP）研究中的挑战病毒，以确定疫苗诱导免疫是否对单一遗传亚型内的多种变异以及跨亚型具有活性，而且可以提高我们对HIV诱导免疫缺陷发病机制的理解，从而推动治疗、预防和治愈的进展。拟议的项目利用Cheng-Mayer博士在艾滋病SHIV模型方面和Blanchard博士在非人灵长类动物医学方面的互补专业知识，并建立在我们在HIV-1疫苗和发病机制研究中成功产生R5 SHIV的记录经验的基础上。在目的1中，我们将描述最近获得的晚期SHIVC分离物的粘膜传播能力，持久维持慢性病毒血症，并诱导疾病与巨细胞脑炎和辅助受体转换的发展一致。在目标2中，我们将构建另外三个R5 SHIV分子克隆，表达来自传递者/创始人或早期感染亚型C和CRF_01AE病毒的Envs。我们将通过在印度恒河猴（艾滋病研究中最常用的猴子物种）中进行四次快速连续传代来适应和提高它们在体内的复制能力。将监测晚期传代猕猴的疾病发展。在目标3中，我们将通过评估从C亚型和CRF_AE SHIV传代猕猴中恢复的无群细胞病毒作为攻击病毒的适用性，评估它们的粘膜传播性和诱导慢性病毒血症和免疫缺陷的能力。

DESCRIPTION (provided by applicant): The goal of this R24 application is to generate a panel of reliable pathogenic R5 SHIVs representing globally circulating HIV-1 strains, with emphasis on subtype C and CRF_AE that are fueling the HIV-1 pandemic. We envision that these novel SHIVs which recapitulate the immunopathogenesis of HIV in humans will serve as valuable resources not only as challenge viruses in preclinical nonhuman primate (NHP) studies to determine if vaccine-induced immunity has activities against multiple variants within a single genetic subtype as well as across subtypes, but to improve our understanding on the pathogenesis of the HIV-induced immunodeficiency to advance progress towards treatment, prevention and cure. The proposed project leverages the complementary expertise of Dr. Cheng-Mayer in SHIV models of AIDS and of Dr. Blanchard in nonhuman primate medicine, and builds on our documented experience in generating successful R5 SHIVs in HIV-1 vaccine and pathogenesis studies. In aim 1, we will characterize a recently obtained late-stage SHIVC isolate for its ability to transmit mucosally, maintain chronic viremia durably and induce disease consistently with development of giant cell encephalitis and coreceptor switching. In aim 2, we will construct three additional R5 SHIV molecular clones expressing Envs from transmitter/founder or early infection subtype C and CRF_01AE viruses. We will adapt and improve their replicative capacity in vivo by performing four rapid serial passages in Indian rhesus macaques, the most commonly used monkey species for AIDS research. Development of disease in the late passage macaques will be monitored. In aim 3, we will evaluate the suitability of swarm cell-free viruses recovered from the subtype C and CRF_AE SHIV passage macaques with disease as challenge viruses by assessing their mucosal transmissibility and ability to induce chronic viremia and immunodeficiency. We believe the potential impact of the resources is substantial. Resource applications include: (1) development of tools for AIDS vaccine research in NHPs; (2) development of tools for preclinical pre-exposure prophylaxis (PrEP), therapeutic and cure studies; (3) investigation of the interaction between HIV-1 subtype and the immune system during acute and chronic infection; (4) investigation of the impact of HIV-1 subtype on AIDS pathogenesis. We envision the R5 SHIVs and models generated will guide vaccine design and development, generate new hypotheses and experiments in AIDS pathogenesis to advance basic and translational discovery research, and facilitate preclinical research in HIV prevention, therapeutics and cure.